Basically substituted derivatives of 11 hquinoxalino [2.3-b]-p-benzothiazines



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Unite 3,010,961 BASICALLY SUBSTITUTED DERIVATIVES F 11 H- QUENGXALINO{2.3-b1-p-BENZO'IHIAZINES Walter Schindler, Riehen, near Basel, and HansJakob Peter-ii, Mnnchenstein, Basel Land, Switzerland, assignors toGeigy Chemical Corporation, Ardsley, N.Y., a corporation of Delaware NoDrawing. Filed Jan. 20, 1960, Ser. No. 3,483 Claims priority,application Switzerland .Fan. 21, 195? 7 Ciaims. (Cl. 260-243) Thepresent invention concerns new heterocyclic compounds which havevaluable pharmacological properties, as well as processes for theproduction thereof.

Basically substituted derivatives of llH-quinoxalino-[2.3-b1-p-benzothiazine have not been known up to now. It has now beenfound that N-derivatives of such compounds corresponding to the generalformula Y. YGLY.

radical Z-Am at a nitrogen atom and additional linkage from O atom tothe other nitrogen atom wherein Y and Y represent hydrogen or halogenatoms, in particular chlorine or bromine,

Z represents an alkylene radical having 2-6 carbon atoms of which 2-4are in the direct linkage between N and Am, and

Am represents a low molecular dialkylamino group,

in the presence of a condensing agent, with a reactive ester of an aminoalcohol of the general formula wherein Y Y Z and Am have the meaningsgiven above.

Sodium amide, lithium amide, potassium amide, sodium or potassium, butyllithium, phenyl lithium or lithium hydride are particularly suitablecondensing stem "ice

or absence of an inert organic solvent, of which benzene, toluene andxylenes can be named as examples.

Particularly the halides are used as reactive esters of amino alcoholsof the general Formula Ii; individually can be named:

Dimethylaminoethyl chloride, diethylaminoethyl chloride,methylethylaminoethyl chloride, B-dimethylaminopropyl chloride,,B-dimethylamino-isopropyl chloride, 'y-dimethylaminopropyl chloride,E-dimethylamino-butyl chloride, rx-methyl 'y dimethylamino-n-amylchloride, fl-(di n propylamino) -ethyl chloride,fl-(methyl-isopropylamino)-ethyl chloride, 8-(di-n-butylamino)-ethylchloride, j3-(diisobutyl-am-ino)-ethyl chloride, pyrrolidino ethylchloride, piperi-dino ethyl chloride, 'y-piperidino propyl chloride,morpholino ethyl chloride, fi-(4-methylpiperazino) ethyl chloride,,8-(4-acetoxyethyl piperazino)-ethyl chloride, 7 (4acetoxyethyl-piperazino)- propyl chloride and1-rnethyl-piperidyl-(3)-methyl chloride as well as the correspondingbromides and iodides.

1lH-quinoxalino[2.3-b]-p-benzothiazine was first produced by G. Walter,R. Htibsch and H. Pollak, Monatsh. f. Chemie 63, 186 (1933), by reactingZ-a-minothiophenol with 2.3-dichloroquinoxaline. If, instead of2-aminothiophenol, a halogen substituted compound, for exampleZ-amino-S-chlorothiophenol, and/or a 2.3-dichloroquinoxaline halogensubstituted in the benzene nucleus is/ are used as starting compounds,halogen substituted 11H quinoxalino[2.3-b]-p-benzothiazines such as,e.g., 3-chloro-llH-quinoxalino[2.3-b]-p-benzothiazine, are obtained inan analogous manner.

In addition, the new heterocyclic compounds of the general Formula I arealso produced by reacting a reactive ester of a compound of the generalformula Y IV radical ZOl-I at a nitrogen atom and additional O-N linkagefrom O atom to the other nitrogen atom in particular a halide, withasecondary amine of the general formula Am-H V wherein Y Y Z and Am havethe meanings given above, there being naturally no linkage between analkyl radical of Am and Z. The reaction can be performed for example ata moderately raised temperature of eg, in an inert solvent such as,e.g., a low molecular alkanol or allranone; advantageously an excess ofthe amine to be reacted is used as acid binding agent. Sometimes thereaction is performed in a closed vessel depending on the boiling pointof the amine and solvent used and also on the reaction temperaturenecessary. Reactive esters of compounds of the general Formula III areobtained, for example, by reacting alkali metal compounds with alkyleneoxides and reacting the hydroxyalkyl derivatives obtained with inorganicacid halides,

agents. The reaction can be performed in the presence methane sulphonicacid chloride or aryl sulphonic acid chlorides, whereupon x-halogenalky1-, x-methane sulphonyloxyalkylorx-arylsulphonyloxyalkyl-xH-quinoxalino [2.3-b]-p-benzothiazines areobtained. Herein x represents one of the positions 11 and 12. The above3 mentioned compounds are reacted, for example, with dimethylamine,methylethylamine, diethylamine, di-n-butylamine, pyrrolidine,piperidine, morpholine, 4-methyl piperazine or 4-acetoxyethylpiperazine.

Finally compounds of the general formula Z Am Ia wherein Y Y Z and Amhave the meanings given above,

are obtained by condensing an N-substituted o-aminothiophenol of thegeneral formula the condensation being performed in the presence of anacid binding agent, or condensing the thiophenol of the general FormulaVI above with a 2.3(1H.4H)-dioxoquinoxaline of the general formula a. Yi l These condensations are performed, for example, in a higher boilingorganic solvent such as o-dichlorobenzene at or in the region of itsboiling temperature. For example, sodium or potassium carbonate can beused as acid binding agent and the water formed in the reaction thereofwith the hydrogen chloride liberated is, for example, azeotropicallydistilled oif.

The tertiary bases form salts some of which are water soluble withorganic or inorganic acids such as hydrochloric acid, hydrobromic acid,sulphuric acid, phosphoric acid, methane sulphonic acid, ethanedisulphonic acid, acetic acid, succinic acid, fumaric acid, maleic acid,malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid andphthalic acid.

The following examples further illustrate the production of the newcompounds. Parts are given therein as parts by weight and theirrelationship to parts by volume is as that of grammes to cubiccentimetres. The temperatures are in degrees centigrade.

Example 1 25 parts of 1lH-quinoxalino[2.3-b]-p-benzothiazine and 17parts of 'y-dimethylamino-propyl chloride are dissolved in 250 parts byvolume of anhydrous benzene and a suspension of 44 parts of sodium amidein toluene'is added dropwise while stirring at 5060. The reactionmixture is warmed for 1 hour at 60 and then refluxed for 18 hours. Aftercooling, water is added, the benzene phase is removed and extracted fourtimes with 25 parts by volume of 2 N-hydrochloric acid each time. Thecombined hydrochloric acid extracts are made alkaline whereupon the x-(y-dimethylamino-propyl)-xH-quinoxalino[2.3-b] p-henzothiazineprecipitates in the form of yellow crystals. It is filtered off undersuction, washed with water and dried. After recrystallising twice frompetroleum ether, it melts at 84-85 propyl) -xH-quinoxalino [23-h] pbenzothiazine (M.P. 125) are obtained in an analogous manner. Thehydrochloride of x-('y-pyrrolidino-Bfi-dimethyl-propyl)-xH-quinoxalino[2.3-b]-p-benzothiazine (M.P. 264") is obtained if the crudebase precipitated from the hydrochloric acid extract producedanalogously to the above example is taken up in ether and the etherealsolution is treated with hydrogen chloride.

On the other hand, on using 3-chloro-l1H-quinoxalino-[2.3-b]-p-benzothiazine as heterocycle, x-(q-dimethylamino propyl) 3chloro xH quinoxalino[2.3 h]- p-benzothiazine is obtained in ananalogous manner. In the above compounds, one of the two positions 11and 12 is meant by x. The ll-position of the hydrogen atom in the parentsubstance is given by G. Walter et al.

Example 2 200 parts of water and 200 parts of 33% caustic soda. lye areadded while cooling to 76 parts of dimethylaminopropylchloride-hydrochloride and the liberated base is separated by extractionwith benzene. 60 parts of benzthiazolone-Z are added to the anhydrousbenzene solution and, at 60, a suspension of 20 parts of sodium amide inbenzene is added. After refluxing for 4 hours, 70 parts of water'areadded and the benzene phase is separated. After evaporating otf thebenzene the residue is distilled. The 3-dimethylamino-propylbenzthiazolone-Z boils at l60162 under 0.03 mm. pressure.

30 parts of potassium hydroxide in 100 parts of ethanol are added to asolution of 38 parts of the above benz thiazolone derivative in 100parts of ethanol, the addi tion being made in a nitrogen atmosphere, andthen the whole is refluxed for 30 minutes. The mixture is diluted with30 parts of water, neutralised with concentrated hy-' drochloric acidand buffered with 10 parts of ammonium chloride. TheN-('y-dimethylamino-propyl)-o-aminothio phenol formed is extracted withether and condensed direct with 2.3-dichloroquinoxaline.

38.7 parts of the crude product are dissolved in 130 parts ofo-dichlorobenzene with 25.8 parts of 2.3-dichloroquinoxaline, 38.7 partsof anhydrous sodium carbonate are added and the whole is refluxed. Thewater formed is azeotropically distilled otf. After cooling, undissolvedparticles are filtered off and washed with o-dichloroben- On using thecorrespondingly basically substituted alkyl V bene. The filtrate isextracted with diluted hydrochloric acid, the acid extraction isseparated and made alkaline with soda lye. The crystals ofl2-('y-dimethylamino-pro-' pyl)-l2H-quinoxalino[2.3-b]-p-benzothiazinewhich precipitate are recrystallised twice from petroleum ether. Thesolution has a strong green fluorescence. The melting point is 91.

Of particular value are those compounds according to Formula I wherein Yand Y each represents hydrogen and Am represents a iower dialkylamino,pyrrolidino or morpholino group.

What we claim is:

1. A member selected from the group consisting of a heterocycliccompound of the formulae Z-Am In and {ii a N N i-Am Ib wherein Y; and Yeach represent a member selected from the group consisting of hydrogen,a chlorine and bromine atom,

Am represents a member selected from the group consisting of lowerdialkylamino, l-pyrrolidino, l-piperi- 5 dine and l-morpholino,

and the hydrochlorides thereof.

2. 12 ('y dimethylanfino-propyl) 12H-quinoxalino-[2.3-b]-p-benzothiazine.

3. 11 ('y dimethyl-amino propyl) 11H quinoxa1ino[2.3-b]-p-benzothiazine.

4. 11 ('y morpholino-propyl) 11H quinoxalino- [2.3-b1-p-benzothiazine.

6 5. 12 (,B dimethylamino ethyl) 12H quinoxalino-[2.3-b]-p-benzothiazine.

6. 12 ('y morpholino propyl) 12H quinox-ali-no- [2.3-b]-p-benzothiazine.

7. The hydrochloride of12-('y-pyrrolidino-flfi-dimethylpropyl)-12Hquinoxa1ino[2.3 -b]-p-benzothiazine.

Walter et a1.: Monatsh., vol. 63, p. 187 (1933).

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A HETEROCYCLICCOMPOUND OF THE FORMULAE